Microbiologically active quaternary ammonium compounds



3,361,793 MICROBIOLOGICALLY ACTIVE QUATERNARY AMMONIUM COMPOUNDS Reginald L. Wakeman, Philadelphia, Pa., and Joseph F.

Coates, Washington, D.C., assignors, by mesne assignments, to Millmaster Onyx Corporation, New York, N.Y., a corporation of New York No Drawing. Filed Feb. 10, 1964, Ser. No. 343,448 14 Claims. (Cl. 260-501.15)

The present invention has for its object the preparation of water-insoluble, microbiologically active compounds by reaction of certain quaternary ammonium hydroxides or their water-soluble salts with aromatic dior poly-carboxylic acids or their water-soluble salts.

The quaternary ammonium compounds used in the process of this invention contain at least one carbon chain having from 8 to 22 carbon atoms and also possess at least one benzyl radical attached to the quaternary nitrogen atom. The benzyl radical may, if desired, be substituted by alkyl groups or halogen atoms. The quaternary ammonium compounds, moreover, possess only non-heterocyclic nitrogen atoms. In general, the quaternary ammonium compounds used in the present invention comply with the formula:

. R CH3 where R is an alkyl radical containing from 8 to 22 carbon atoms or an alkyl benzyl radical in which the benzyl group may contain a substituent methyl radical and in which the alkyl group contains 8 to 22 carbon atoms and R" is a benzyl or substituted benzyl radical or a methyl group if R is an alkyl benzyl radical containing eight or more carbon atoms in its alkyl substituent. X in the above formula is chlorine, bromine, iodine, sulfate, methosulfate, ethosulfate and the like.

Typical examples of these quaternary ammonium compounds are alkyl dimethyl benzyl ammonium chloride in which the alkyl group may have from 8 to 22 carbon atoms, alkyl dimethyl substituted benzyl ammonium chlorides in which the alkyl radical contains from 8 to 22 carbon atoms and in which the benzyl radical is substituted with one or more side chains containing from 1 to 4 carbon atoms such, for example, as methyl, dimethyl, trimethyl, tetramethyl, ethyl, diethyl, isopropyl and tertiary butyl or with one, two, or more, halogen atoms such as chlorine and bromine, alkyl dimethyl menaphthyl ammonium chloride and alkyl dimethyl tetrahydromenaphthyl ammonium chloride in which the alkyl radical contains from 8 to 22 carbon atoms, alkyl benzyl trimethyl ammonium chloride in which the alkyl radical contains from 8 to 22 carbon atoms and in which the aromatic nucleus of the benzyl radical may, if desired, be substituted by one or more methyl or other lower alkyl groups and mixtures of the aforesaid quaternary ammonium compounds.

In general, we prefer to use such quaternary ammonium compounds which have a phenol coeflicient of at least 100 with respect to both Staphylococcus aureus and 3,363,79 ttented Jan. 2, 1%68 where R is a benzene or naphthalene nucleus or the nu cleus of. diphenyl, diphenyl oxide or diphenylene oxide. R may contain one or more chloro, bromo, iodo. amino, nitro, sulfo or hydroxyl radicals. It may also contain one or more alkyl radicals having from 1 to 22 carbon atoms.

Typical examples of the aromatic dior poly-carbon ylic acids which may be used in the practice of this in vention include phthalic acid, isophthalic acid, ter ephthalic acid, tetrachlorophthalic acid, 3chloro phthalic acid, 4-chloro phthalic acid, 3-nitro phthalic acid, 4-nitro phthalic acid, 3-hydroxy phthalic acid, the alkyl phthalic acids in which the alkyl radical contains from 1 to 22 carbon atoms, the polyalkyl phthalic acids in which the total number of carbon atoms in the alkyl radicals is between 2 and 22, the sulfo phthalic acids, hemimellitic acid, trimellitic acid, trimesic acid, prehnitic acid, n1eil0- phanic acid, pyromellitic acid and various chloro, bromo, hydroxy, sulfo, nitro and mercapto derivatives thereof. mellitic acid, diphenic acid, the diand poly-carboxylic acid derivatives of diphenylene oxide, the diand poly carboxylic acid derivatives of diphenyl oxide, the chloro. bromo, hydroxy, sulfo, nitro, mercapto and amino derivatives of these acids, naphthalene-l,2-dicarboxylic acid, naphthalene-1,4-dicarboxylic acid. naphthalcne-l,5- dicarboxylic acid and the like.

The compounds of this invention may be prepared by mixing aqueous solutions of the quaternary ammonium salts or hydroxides with an aqueous solution of the acid in question or any of its water-soluble salts. The ratio of quaternary ammonium compound to acid should be such as to permit complete salt formation between the quaternary ammonium compound and all of the carboxylic acid groups of the aromatic di or poly-carboxylic: acid, that is to say, the cationic and the anionic components should be mixed in stoichiometric quantities. Where another radical containing an acidic hydrogen is present. in the compound such, for example, as in the sulto group or hydroxyl group, sutficient quaternary ammonium com pound may, if desired, also be employed in quantities so as to form the quaternary ammonium salt with such radical in addition to quaternary salt formation with all of the carboxylic acid groups.

After thorough mixing, the organic product layer is separated from the aqueous layer (as with a separfltory funnel) since two distinct phases are formed. Separation may be facilitated by the addition of an organic solvent immiscible with water. The product layer may be washed with water to remove any residual by-product salt or on reacted materials. The solvent, if any, may be evaporated and the product air or vacuum dried to a paste, wax, oil or solid.

It is not necessary to use an aqueous medium. Any solvent or solvent mixture in which the starting materials are soluble will be satisfactory. Non-aqueous solsterility 'ents facilitate the separation of by-produet inorganic salt .nd reduce the need for vacuum drying to get an anhyirous product. When a non-aqueous medium is employed, t is usually necessary to add a small amount of water facilitate ionic reaction.

The product may be used, if desired, without drying ince any entrapped water is irrelevant to the microiological activity of the compounds. in other applicaions, removal of water may be essential for reasons not elated to biological activity.

An alternative method for the preparation of comounds especially applicable to the treatment of fabric, opes, net, woven and non-woven fabric and reticulated r convoluted materials, involves a two-step process. In he first step, the material is passed through a bath conaining the anionic moiety. Excess solution is removed y methods well known to those skilled in the art. The reated material is then passed through a second bath therein the concentration of quaternary ammonium comound is such that the material pickup will result in an quivalent amount of quaternary ammonium compound eacting with the anionic moiety, depositing the product 1 the most intimate way on the surface and in the in- :rstices, convolutions and iecticulations of the material.

The method of adjustment of solution concentration '1 achieve the required pickup is well known to those killed in the art. The order of treatment may be reersed without attecting the biological activity or dura ility of the product on the material. The products of its invention may be formulated as water dispersions y dissolving them in a water-miscible organic solvent .ich as acetone or methanol and diluting with water or y dissolving them in emulsifiable oils such as, for examle, sulfonated castor oil or pine oil and diluting with 'ater. In preparing aqueous dispersions, emusifying gents such, for example, as ethylene oxide condensates f alkyl phenols may be used with or without organic DlVClliS.

it is surprising that the compounds of this invention xhibit high microbiological activity despite their relative solubility in water. Because of their unusual combinaon of physical and microbiological properties, they can e used to impart laundry-resistant anti-microbial char- :tcristics to textiles. They can also be used as the active gent in antimildew finishes for textiles which are restant to teaching with water.

Although the compounds have low water solubility, icy are compatible with various organic solvents, plastizers and high molecular weight compounds, Conseucntly, they may be incorporated as anti-microbial agents l synthetic resins and plastics. The compounds are com atible with natural and synthetic rubber latices. Therere, they may be used to prepare bacteriostatic films and toided objects deposited from such latices.

The compounds can be incorporated into cutting and hiding fluids without precipitation. Also, they blend well ith non-ionic and anionic surface active agents. in such .impositions they retain their microbiological activity.

it. will be understood that the properties of the prod :ts described herein will vary depending upon the nature 1'' the cationic quaternary ammonium compound used l their preparation as well as the anionic compound :acted therewith.

The chemical, physical and biological properties of re products of our invention make them especially apropriate tor the following applications when suitably tcorporated in active amounts in an appropriate vehicle, inder, medium or substrate:

(1) Mildewproofing fabric, canvas, ropes, textiles, wnings, sails, tenting and other woven and non-woven :ticulated materials.

(2) Paint mildewstats.

(3) Jet plane fuel additive to control growth of micro rganisms.

ill

(4) Odor preservative agents for clothes and shoes (5) Mildew retardant and odor suppressant for shoes and other leather products.

(6) Topical antiseptics.

(7) Antidandruft agents. 7

(8) Distinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement. brick and other inorganic building materials, to retard growth of microorganisms, fungi, mold and algae (l i Wool preservative.

(12) Plant and tree spray to combat fungi.

(13) Antimycotic agents for soap wrappers.

(l4) Selfisanitizing brushes.

(l5) Mildewproofing agent in and on plastic and iiim (l6) Mildewproofiing of cellulosics, cardboard, tiber board, paper and cordage.

(17) Contact biostat for application to film, waxes and cloth to preserve cheese, meats and vegetables and other food products.

(18) Algal inhibition, especially on surfaces and in solution where low foaming is desirable.

(19) Paper pulp slime control.

(20) Sanitizing agent for rug, carpet, curtains.

(21) Egg preservation.

(22) Adhesive preservation.

(23) Preservation of latex paints.

(24) Preservation of metal-working compounds,

(25) Additives tor soap and for both anionic and nonionic detergents in liquid. bar, powder, bead, solution and other forms to impart bacteriostatic and t'ungistatic properties thereto.

The microbiological activity of our compounds has been evaluated for microbiological stasis by the Standard Tube Dilution Test. the technique for which is common knowledge to those skilled in the art. A Difco Bacto CSMA Broth #0826 was used in the study. This is used to determine the lowest concentration of microbiologically active compounds which will inhibit the: growth of the organism in question. For a wide range of applications, the inhibition of growth rather than out right kill is satisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of the CSMA Broth in a test tube which is then sterilized in an autoclave. One cc. solution of the micro biologically active compound at an appropriate concen tration is added to the test tube which is then inoculated with 0.1 cc. of. a. twenty-four hour old culture of the organism under study. The test tube is then incubated at EXAMPLE 1 Six hundred grams of a 10% by weight solution oi; the trisodium salt of trimesic acid was prepared. To 300 grams of this solution in a 2 liter separatory tunnel was added 1335 grams of a 10% solution of alkyl dimethyl ethyl-benzyl ammonium chloride (Onyx Chemical Coi poration, ETC-471; alkyl distribution: C C 30%, C 17%, C 3%). The tunnel was shaken and. layer separation allowed to occur. Benzene was added to facilitate layer separation. The organic product layer was separated and the benzene evaporated on a steam. bath. The product was then vacuum dried to give tr't (alkyl dimethyl ethylbenzyl ammonium) trimesate in the form of a white paste grams) in 98% yield;

EXAMPLE II To the remaining 300 grams of the trimesic acid solution of Example I was added 1320 grams of a solution of alkyl dimethyl benzyl ammonium chloride (Onyx Chemical Corporation, BTC824; alkyl distribution: C 60%, C C 5%, C 5%). The mixture was poured into a separatory funnel, well shaken and allowed to stand to permit layer separation. Benzene was added to facilitate layer separation. The organic product layer was separated and dried first on a steam bath and then in a vacuum oven to give a light yellow paste (130 grams) of tri(alkyl dimethyl benzyl ammonium) trimesate in 96% yield.

EXAMPLE III Using the trisodium salt of trimellitic acid in place of the trisodium salt of trimesic acid, the corresponding quaternary derivatives were prepared as above. The alkyl dimethyl ethyl-benzyl ammonium chloride derivative was obtained as a yellow paste in 100% yield. The alkyl dimethyl ethyl-benzyl ammonium) isophthalate as a light yellow paste in 100% yield.

EXAMPLE IV Six hundred grams of a 10% by weight solution of the disodium salt of isophthalic acid was prepared. To 300 grams of this solution in a 2 liter separatory funnel was added 1170 grams of a 10% solution of alkyl dimethyl ethyl-benzyl ammonium chloride (identical to Example I). The funnel was shaken and benzene was added to facilitate layer separation. The organic product layer was separated and the benzene evaporated on a steam bath. The product was then dried to give di(alkyl dimethyl ethyl-benzyl ammonium) isophthalate as a yellow paste in 100% yield (134 grams).

EXAMPLE V To the remaining 300 grams of the isophthalic acid solution of Example IV was added 1070 grams of a 10% solution of alkyl dimethyl benzyl ammonium chloride (identical to that of Example II). The mixture was poured into a 2-liter separatory funnel, benzene added and the funnel well shaken. The organic product layer was separated and dried first on a steam bath and finally in a vacuum oven to give a yellow paste of di(alkyl dimethyl benzyl ammonium) isophthalate in 100% yield (123 grams).

Using identical quantities and conditions, the corresponding quaternary derivatives of terephthalic and phthalic acids were prepared,

EXAMPLE VI Three hundred grams of a 10% solution of the tetrasodium salt of yromellitic acid was prepared and placed in a separatory funnel. Thirteen hundred grams of a 10% solution of alkyl dimethyl ethyl-benzyl ammonium chloride was added and the solutions well mixed. The organic product layer was separated and dried to give 140 grams (100% yield) of a yellow paste consisting of tetra(alkyl dimethyl ethyl-benzyl ammonium) pyromellitate.

EXAMPLE VII Sixty grams of a 10% solution of the trisodium salt of 4-sulpho phthalic acid was prepared and placed in a separatory funnel. Two hundred grams of a 10% solution of alkyl dimethyl ethyl-benzyl ammonium chloride was added and the solutions well mixed. The organic product layer was separated and dried to give 23 grams (95% yield) of a brown paste consisting of tri(alkyl dimethyl ethyl-benzyl ammonium) sulpho phthalate.

The microbiological activity of the products of this invention is illustrated by Table I which shows results obtained by means of the Standrad Tube Dilution Test described above. The performane of the products listed in this table was determined with respect to Staphylococcus 6 aureus (S.a.), Salmonella typhosa (S.t.) and Aspergillus niger (A.n.).

TABLE I Reciprocal of Static Dilution of Product vs.

Compound S.a. S.ti An Di (myristryl l dimethyl benzyl amanium) uhthalate. V, 10 10 10 Di (lauryl 2 dimethyl ethyl-benzyl ammonium) nhthal'ita 10 10 10" Tetra (lauryl dimethyl ethyl-benzyl ammonium) pyrornellitate 10 10 10" Di (lauryl dimethyl ethyl-benzyl ammonium) tereohthalate l0 l0 l0 Di (mvristvl dimethyl benzyl amnmiu :n) terephthalate 1O 10 10 Tri (lauryl dimethyl ethyl-benzyl ammonium) trimellitatc 10* 10' 1 0 'lri (myristyl dimethyl benzyl a'nnonium) trimcllitatc 10 10 10 Di (lauryl dimethyl etliyl-Jcnzyl ammonium) tetrachloro phthala-te.. 10 10 10 Di (myristyl dimethyl benzyl ammonium) tetrachloro phthalatcuu 10 10 10* 1 Technical alkyl blend carrespondi'ig to that given in Example ll. 1 Technical alkyl blend corresponding to that given in Example 1.

Standard tube dilution tests carried out with the product of Example VI showed static dilution levels of 1/75,000 against both Penicillium luteum and Pullztlaria pullulans. Its activity against these organisms shows it to be a useful fungicide for incorporation in both solvent type and latex type paints.

Di(lauryl dimethyl ethyl-benzyl ammonium) terephthalate, prepared according to Example IV, was found to inhibit the growth of Alternaria, Penicillium digitatum, and Diamhus fusarium at 1% concentrations. This compound is also effective at concentrations as low as 0.1% in the control of the Mexican bean beetle without evidence of phytotoxicity to the host plant. Incorporated in wallboard joint cement sensitive to mold growth, this compound completely prevented the development of mold during a three week test period when panels of joint cement containing 0.2% of this additive were confined in a desiccator under humid conditions together with moldy panels containing no inhibitor serving as a source of contamination.

Tetra(lauryl dimethyl ethyl-benzyl ammonium) py-- romellitate, prepared according to Example VI, is effective, at concentrations of 500 parts per million, in the control of southern bean mosaic virus on pinto bean plants. It may also be used to prevent germination of the seeds of certain types of weeds.

In combination with soap and synthetic detergents of both anionic and non-ionic character, the compounds of this invention may be used to impart bacteriostatic and fungistatic properties to cleansing materials in bar. bead, flake, powder, liquid, or solution form.

We claim:

1. A compound having the structure:

wherein R is a member of the group consisting of alkyl containing 8 to 22 carbon atoms, alkyl benzyl wherein the alkyl contains 8 to 22 carbon atoms and alkyl methylsubstituted benzyl wherein the alkyl contains 8 to 22 carbon atoms, wherein R" is a member of the group consisting of benzyl, lower alkyl-substituted benzyl, and methyl, R" being methyl when R is alkyl benzyl, wherein R is a member of the group consisting of substituted and unsubstituted benzene, naphthalene, diphenyl, diphenyl oxide and diphenylene oxide wherein the substituents are selected from the group consisting of chlorine, bro mine, iodine, amine, nitro, sulfo, hydroxyl and alkyl of, l to 22 carbon atoms, and wherein x is at least 1.

2. Di(myristyl dimethyl benzyl ammonium) phthalate.

3. Di(lauryl dimethyl ethyl henzyl ammonium) phthalate.

4. Tetraflauryl dimethyl ethyl benzyl ammonium) pyromellitate.

5. Di(lauryl dimethyl ethyl benzyl ammonium) terephthalate.

6. Di(myristyl dimethyl benzyl ammonium) terephthzilatc.

7. Tri(lauryl dimethyl ethyl benzyl an'imonium) trimellitate.

8. Tri(myristyl dimethyl benzyl ammonium) trimel litate.

9. Di(lauryl dimethyl ethyl benzyl ammonium) tetraehlorophthalate.

10. Di(myristyl dimethyl benzyl ammonium) tetrachlorophthzilate.

11. Tri(alkyl dimethyl ethyl benzyl ammonium) sulphophthalate, wherein the alkyl group contains l2 to l8 carbon atoms.

12. Di(alkyl dimethyl benzyl ammonium) isophthalate. wherein the alkyl group contains 12 to 18 carbon atoms.

13. Tri(2ilkyl dimethyl benzyl ammonium) trimesate, wherein the alkyl group contains 12 to l8 carbon atoms..

UNlTED STATES PATENTS 2.108.765 2/1938 Domagk Z6()567.6 2,676,986 4/l954 Nukeman et al. v- 260--567.6 2,769,731 l0/l956 Schneid et a1. 260-438.l

OTHER REFERENCES Muccacaro et 11]., Giorn. Microbiol. 8, 65-82 (1966).. C. A. relied on, vol. 55, column 6598' LORRAUVE A. NEiNBERGER. Primary Emmi/lei:

20 M. WEBSTER. Assislulzl Examiner. 

1. A COMPOUND HAVING THE STRUCTURE: 